Iron Metabolism in Ts65Dn mice, a Model of Down syndrome - PROJECT SUMMARY/ABSTRACT
Down syndrome (Ds) is a developmental disability that typically results from the triplication of chromosome 21
with an occurrence of 1 in 700 live births. Chromosome 21 triplication may alter normal gene expression and
lead to intellectual disability, early onset Alzheimer’s disease, congenital heart disease, hematologic disorders,
among other conditions. Dysregulation of iron homeostatic mechanisms may be an underlying factor in clinical
outcomes associated with Ds. Iron is a trace element well-known for its involvement with physiological
processes that include oxygen transport, inflammatory response, energy metabolism, and DNA synthesis.
Iron homeostatic dysregulation in Ds could lead to compromised plasma iron levels and tissue iron
accumulation that catalyzes the production of reactive oxygen radical species (ROS). Despite reports of iron
status parameters in Ds there is a lack of clear and comprehensive understanding of iron homeostatic
regulation among this population of individuals. The Ts65Dn mouse is an established model of Ds that may
hold considerable value to study mechanistic factors that regulate iron homeostasis in Ds. The objective of this
project is to delineate sex and age-related alterations in iron homeostatic regulation over the adult lifespan of
Ts65Dn mice and to associate changes in iron regulation with tissue iron levels and oxidative stress. In these
studies, tissues (brain, liver, and plasma) from Ts65Dn mice and wild-type (WT) colony controls at 3, 12, and
18 months of age will be studied to address two integrated Specific Aims: 1) Depict the iron homeostatic
phenotype of Ts65Dn mice across the adult lifespan, and 2) Determine the impact of hypoxia exposure (10%
inspired O2) on systemic and tissue iron homeostasis, hematologic profile, and tissue oxidative stress in
Ts65Dn mice. The first aim of this proposal will establish the utility of the Ts65Dn mouse model to study iron
status and iron homeostatic regulation in Ds. It is hypothesized that Ts65Dn mice will show greater
inflammation that will promote an iron regulation response leading to lower plasma compartment iron and
elevated iron in the storage compartment. Elevated tissue iron in Ts65Dn mice is postulated to associate with
greater oxidative injury. The second aim will employ hypoxia exposure to alter iron homeostatic regulation of
Ts65Dn and WT mice to test the hypothesis that hypoxia induced iron distribution shifts from storage to the
plasma compartment will reduce Ts65Dn tissue iron toxicity and improve the hematologic profile. Furthermore,
it is hypothesized that male mice will display greater iron status and oxidative stress than females, with Ts65Dn
showing greater levels than WT controls. As iron metabolism dysregulation and tissue iron accumulation can
become more prominent with aging, understanding iron metabolism in Ds is of utmost importance as life
expectancy of this population has dramatically improved over the past several decades.
